PROJECT SUMMARY Extensive evidence demonstrates that individuals that regularly consume high salt diet have a greater risk of developing cardiovascular diseases (CVD) compared to individuals on low salt diet. Moreover, dietary consumption of high salt and the associated inflammation have critical roles in the development of CVD, such as hypertension. Particularly, T cells are intimately linked to the development of hypertension. However there is a gap in our knowledge of the mechanisms involved in salt-mediated T cell activation, end-organ damage and CVD risk. Levels of endothelin-1 (ET-1), a potent vasoactive peptide, are elevated after high salt consumption. Renal inflammation is one of the hallmarks of salt-sensitive hypertension, and ET-1 is known to exert pro-inflammatory actions in renal tissue. In fact, human T cells express ET-1 receptors (ETA and ETB) on their surface and are activated by ET-1 in vitro. Recent reports demonstrate that high salt induces production of pro-inflammatory cytokines by T cells. Despite the many studies demonstrating that the renal ET-1 system is an important contributor to increased blood pressure, inflammation and kidney damage during high sodium intake, the molecular mechanisms by which ET-1 mediates these effects remain obscure. Further, the involvement of ET-1 in renal T cell activation and target organ damage during salt-dependent hypertension needs investigation. High salt consumption increases ET-1 production by several cellular sources in the kidney, although the cellular source of ET-1 mediating renal T cell activation and differentiation during high salt remains unclear. This proposal aims to elucidate novel molecular pathways involved in the control of the renal pathophysiology associated with increased blood pressure. This proposal will test that 1) activation of the ET-1/ETA axis leads to kidney T cell activation during salt-sensitive hypertension and results in salt-induced kidney damage and CVD risk, and 2) elevated vascular endothelium-derived ET-1 is responsible for the kidney damage observed during high salt consumption. With the help of my mentor and scientific advisory team, I will continue on the path toward my long-term goal of developing a strong and independent research program at the intersection of immunology and cardio-renal physiology, with the ultimate goal of translating this knowledge to improve human health. If awarded, this K01 award will help me to achieve extra training to become a successful basic science investigator in the field of cardio-renal physiology.